Bioequivalence Testing in the U.S.

for Generic Drug Products

Shirley K. Lu, Ph.D.

Barbara M. Davit, J.D., Ph.D.
Division of Bioequivalence
Office of Generic Drugs
Center for Drug Evaluation and Research
U.S. Food and Drug Administration
April 18, 2007

Topics for Discussion

z Why FDA requests bioequivalence (BE) studies

z Regulatory authority on BE
z General BE study considerations
z BE approaches: IVIVC, urine, PD, clinical, in vitro
z Biowaivers: IV solutions, oral solutions, solid oral
dosage forms, BCS class I, DESI
z Dissolution data
z Special Cases: Specific examples of actual BE
requirements for certain drug products

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 Why FDA requests BE studies

z To determine rate/extent of absorption of

each therapeutic moiety for
– Potential generic products for which there is a
reference listed drug (RLD) approved for
marketing in US
– Potential new drug products (new salts, dosage
forms) for which adequate clinical studies have
already been conducted
– Reformulated drug products

Regulatory authority on BE

z The United States Food Drug and Cosmetic Act

(FDCA), enacted by Congress, gives authority to FDA
– Provisions for generic drugs added in 1984
z FDCA (§505) states that rate and extent of drug
absorption must be compared to establish
bioequivalence between two products
z The FDA’s regulations are codified in Title 21 of the
Code of Federal Regulations (21 CFR)
z Under 21 CFR (§320.23)
– Use Cmax as index of rate of absorption
– Use total AUC as index of extent of absorption
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 General BE study considerations

z Most studies use healthy normal subjects

– FDA asks that both males, females be enrolled
z Can use patients if there are safety issues
z The number of subjects is based on PK
variability
z A BE study of a highly variable drug may
require enrollment of a larger number of
subjects

General BE study considerations

z If drug poses a safety risk to healthy normal

subjects, must study in patients
z Examples
– Clozapine – evaluate BE in a steady-state study
in schizophrenic patients on established regimens
(See FDA guidance)
– Etoposide – evaluate BE as the first dose of a
treatment cycle in cancer patients

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 General BE study considerations

z Bioanalytical methods must be validated

z Pre-study, should determine the following
– Assay selectivity
– Assay precision and accuracy
– Storage stability of drug in various matrices
– Recovery of drug and internal standard
– Assay limit of quantitation (LOQ)

General BE study considerations

z AUC is determined by the trapezoidal

method
z FDA requests that both AUC0-t and AUC∞
meet BE criteria
z If drug has a long T1/2, then not necessary to
calculate AUC∞
z Cmax and Tmax are determined visually
z Applicants also report Kel and T1/2

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 General BE study considerations

z Use ANOVA with two one-sided tests procedure to

statistically analyze BE study data (Schiurmann, J
Pharmacokinet Biopharm 1987;15:657)
z BE criteria are that 90% confidence intervals of
geometric mean AUC and Cmax T/R ratios must fall
within 0.8 to 1.25
z Rounding up or down is not permitted
z OGD may also evaluate Tmax if rapid onset of effect is
necessary for efficacy

Single-dose fasting BE study

z Most sensitive and discriminating form of BE

study design
z FDA requests single-dose fasting BE study for
all systemically available/active drug unless
precluded for safety reasons
– Example: Mefloquine tablets, 250 mg
– For reasons of safety, label recommends that
patients take on empty stomach
– FDA requests
z Single dose, parallel design fed BE study
z Stop plasma sampling at 72 hours
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 Single-dose fed BE study

z For most solid oral dosage forms, sponsor

should conduct both fasted & fed BE studies
z Drug is given within 30 minutes of consuming a
high-fat meal
z Meal should contain at least 50% of Kcal as fat
and provide 800-1000 Kcal

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When OGD requests fed BE

z For immediate-release (IR) products,

dictated by FDA-approved label for the RLD
z If label contains statements about effect of
food on absorption or administration
z If drug cannot be given on an empty stomach
(for safety reasons)

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 When OGD requests fed BE

z For all orally-administered modified-release

(MR) oral drug products
– Delayed-release (DR)
– Extended-release (ER)
– To compare potential for dose-dumping
z Not necessary to conduct fed BE studies for
all strengths of MR tablets

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When OGD does not request fed BE

z When the label advises that the drug must be

taken on an empty stomach
z When the label makes no statements about
effect of food on absorption or administration
of an IR product
z When the drug is in BCS Class I (applies
only to IR products)

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 BE Approaches

z Listed in 21 CFR §320.24, in descending

order of accuracy, sensitivity, reproducibility
1. Pharmacokinetic (PK) study in which drug
concentrations are measured in plasma
z In vitro-in vivo correlation (IVIVC)
2. PK study in which drug concentrations are
measured in urine

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BE Approaches (continued)

3. Acute pharmacologic effect measured as a

function of time (BE study pharmacodynamic
or “PD” endpoints)
4. Well-controlled clinical trial (BE study with
clinical endpoints)
5. Currently available in vitro test
6. Any other approach deemed adequate by
FDA

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 Pharmacokinetic Clinical/PD
Dosage Form Measurement Measurement
Performance

Dosage Drug in Site of Therapeutic

Gut Wall Blood
Form Solution Activity Effect

Depiction of a Model
of
Oral Dosage Form
Performance
Dose ln Dose

BE Approaches: IVIVC

z The in vitro-in vivo correlation (IVIVC)

– Develop formulations with differing release rates
and correlate in vitro dissolution with in vivo
absorption
– If an IVIVC is established, can waive in vivo
studies in some circumstances
– Evaluate both internal and external predictability

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 BE Approaches: Urine

z Urine measurements are appropriate when

drug cannot be reliably measured in plasma
z Example: potassium chloride (KCl)
z Baseline in blood is too high to permit
accurate measurement

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Special Case: IR tablet, drug cannot be

detected accurately in plasma

z Alendronate tablets, available in strengths of 5, 10,

35, 40, 70 mg
z Problems with plasma detection because of low
concentrations and redistribution from bone
z Food markedly reduces bioavailability
z FDA requests single-dose fasting study on 70-mg
strength, measurement of alendronate in urine
z FDA will consider granting biowaivers on 5-, 10-, 35-,
40-mg strengths

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 BE Approaches: PD

z The FDA accepts PD effect methods to

approve generic topical corticosteroid drug
products
z This approach is based on ability of
corticosteroids to produce vasoconstriction or
blanching in skin
z FDA posts a guidance on this approach

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Special Case: Topical Corticosteroid

z Clobetasol propionate 0.05% gel for

z Clobetasol is a medium potency steroid
z In pilot study using application of the RLD to
arm, ED50 was about 20 minutes
z In pivotal study, investigators do the following
– Apply test and reference to arms for 20 minutes
– Monitor blanching response of skin for 24 hours
after cream removed
– Perform BE statistics on the AUEC metric

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 BE Approaches: Clinical

z BE studies with clinical endpoints

z For drug products that are not systemically absorbed
z Examples
– Topical drug products
– Some locally acting GI drug products
z Designs are randomized, blinded, balanced, parallel
z Patients receive test, reference, placebo
z Placebo group used to ensure that patients respond
to test and reference product

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Special Case: Topical Acne Gel

z Tretinoin gel, available in strengths of 0.025,

0.05, 0.1%
z FDA requested BE studies with clinical
endpoints on the 0.025% and 0.1%
– Endpoint related to healing of lesions
z FDA granted a biowaiver on the 0.05%
strength
– Based on fact that all strengths were
proportionally similar

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 BE Approaches: In Vitro

z In vitro approaches are also used with locally

active drug products
– Oral cholestyramine suspensions, tablets,
capsules
– Nasal sprays and suspensions

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Waivers of in vivo testing

(biowaivers)

z Set forth in 21 CFR Part 320

z IV solutions
z Lower strengths of solid oral dosage forms
z Oral solutions
z BCS Class I drugs
z DESI drugs with no bioequivalence problems

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 Biowaivers – IV solutions

z Set forth in 21 CFR §320.22(b)(1)

z A parenteral solution intended for injection, or an otic
or ophthalmic solution
z Must contain the same active and inactive
ingredients in the same amounts as the RLD
– Quantitatively (Q1) and qualitatively (Q2) the same
z Example: Levocarnitine for injection, 200 mg/mL
– FDA requests
z Composition should be the same as that of the RLD
z Companies submit CMC, labeling, and formulation data in
support of biowaiver request
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Biowaivers – oral solutions

z Set forth in 21 CFR §320.22(b)(2)

z A generic oral solution can contain different
excipients than the RLD
z Formulation must not contain an excipient that will
significantly affect absorption of the active ingredient
z Example: Prednisolone phosphate oral solution
– To document BE, FDA requests composition data on the
generic product
– Generic composition can be different from RLD composition
– Inactive ingredients should not have safety issues

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 Biowaivers – solid oral forms

z Set forth in 21 CFR §320.22(d)(2)

– Acceptable in vivo BE must be established for one strength
(generally the highest strength)
– Dissolution testing must be acceptable
– Strengths must be proportionally similar
z For safety reasons, OGD may request an in vivo study on
a low strength, and grant biowaivers on higher strengths
z Example: Terazosin hydrochloride tablets, available in 1-,
2-, 5-, 10-mg strengths
– Because of safety concerns, FDA requests fasting and fed BE
studies on the 2-mg strength
– FDA will consider granting biowaivers on 1-, 5-, 10-mg strengths

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Biowaivers-BCS Class I

z Highly soluble
– An amount of drug comparable to highest strength must be
soluble in 250 mL of solution over wide pH range
z Highly permeable
– Can be established by in vivo or in vitro methods
z Rapidly dissolving
– At 0.1N HCl, pH 4.5 and 6.8 buffers, 900 mL, using paddles at
50 rpm or basket at 100 rpm
z Example: Ofloxacin tablets
– Oral bioavailability > 95%
– Solubility > 400mg/250 mL
– Dissolution is rapid at pH 1.2, 4.5, and 6.8
– FDA designated as BCS Class I and granted biowaiver

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 Biowaivers-DESI

z Drug efficacy study implementation was conducted in

the 1970s
z Panel of scientific experts conducted study
z In vivo BE studies can be waived for solid oral dosage
forms that meet these criteria
– Approved before 1962 in US
– Determined to be efficacious by DESI panel
– No bioequivalence problems
– Dissolution data must be acceptable
z Example: Nystatin tablets (meet all the above criteria)
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Dissolution data

z The Division of Bioequivalence (DBE) at OGD is

responsible for determining optimal method and setting
specifications for generic drugs
z FDA method used for IR and DR products
z Case-by-case method development for ER drug products
z Use dissolution data to support requests for biowaivers of
lower strengths
z Example: FDA requests the following for omeprazole DR
capsules (24 capsules per dissolution test)
– Two-stage dissolution testing
– Acid media for two hours
z Must test residual omeprazole in capsules
– Buffered media for the duration of dissolution testing
– FDA will consider granting biowaiver on 10-mg strength
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 Summary and conclusions

z The FDCA and FDA regulations give the FDA

the legal authority to request BE studies
z FDA posts guidances on BE approaches:
http://www.fda.gov/cder/guidance/
z For most systemically available/active generic
drugs, FDA requests a single-dose fasting and a
single-dose fed BE study
z Applicants can request waivers of in vivo testing
provided they meet FDA criteria

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Special Case: ER Tablet, all strengths

proportional

z Verapamil hydrochloride ER tablet is available in

120, 180, 240 mg strengths
z All strengths are proportionally similar
z FDA requests
– Single-dose fasting and fed BE studies on the 240-mg
strength
– Acceptable dissolution testing in at least 3 media on 120-,
180-, 240 mg strength
z FDA will consider granting biowaiver on 120-, 180-
mg strengths

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 Special Case: IR Tablet, all strengths
not proportional

z Cilostazol tablets
z 50-, 100-mg strengths are not proportionally
similar
z FDA requests the following
– Acceptable fasting and fed BE studies on the 100-
mg strength
– Acceptable fasting BE study on the 50-mg
strength

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Special Case: DR Capsule, all

strengths not proportional

z Omeprazole DR capsules, available in 10, 20, 40 mg

strengths
z The 20- and 40-mg strengths are not proportionally
similar
z The label recommends opening capsule and
sprinkling on applesauce
z FDA requests the following for omeprazole DR
capsules
– Single-dose fasted and fed in vivo BE studies on the 40-mg
strength
– A single-dose fasted BE study on the 20-mg strength
– An applesauce study on the 40-mg strength

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 Special Case: NTI drugs

z Levothyroxine
z Available in strengths of 0.025, 0.05, 0.075,
0.088, 0.1, 0.112, 0.125, 0.137, 0.15, 0.175,
0.2, 0.3 mg
z FDA requests fasting and fed BE studies on
the 0.3-mg strengths
z FDA will consider granting biowaivers on all
other strengths

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Special Case: Oral Suspension

z Megestrol acetate oral suspension, available

in strength of 40 mg/mL
z Label does not mention food effect on
megestrol absorption or PK
z FDA requests fasting BE study on a single
dose of suspension (20 mL)
z Dissolution testing should be done on 12 20-
mL samples (one dosage unit)
z Dissolution testing uses paddles at 25 rpm
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 Special Case: IR Microemulsion

z FDA requests the following for cyclosporine

IR capsules
– Single-dose fasting and fed BE studies with
administration in orange juice, water or milk, on
the 100-mg strength
– Single-dose fasting BE study with administration
in apple juice on the 100-mg strength
z FDA will consider granting biowaivers on 25-
and 50-mg strengths

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Acknowledgements

z Barbara M. Davit, J.D., Ph.D., Deputy

Director DBE
z Dale Conner, Pharm.D., Director DBE
z Lizzie Sanchez, Pharm.D., Special Assistant
to the Director

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